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Clinically Relevant Gene Editing in Hematopoietic Stem Cells for the Treatment of Pyruvate Kinase Deficiency Hemolytic Anemia

By Sara Fañanas Baquero, Oscar Quintana-Bustamante, Daniel Patrick Dever, Omaira Alberquilla, Rebeca Sanchez, Joab Camarena, Isabel Ojeda-Pérez, Mercedes Dessy Rodríguez, Rolf Turk, Mollie S. Schubert, Jose Luis Lopez Lorenzo, Paola Bianchi, Juan Antonio Bueren, Mark A Behlke, Matthew Porteus, Jose Carlos Segovia

Posted 15 Jan 2021
bioRxiv DOI: 10.1101/2021.01.14.426673

Pyruvate Kinase Deficiency is an autosomal recessive disorder caused by mutations in the PKLR gene, causing chronic non-spherocytic hemolytic anemia. PKLR gene encodes for the erythroid pyruvate kinase protein (RPK) implicated in the last step of the anaerobic glycolysis in erythrocytes. The defective enzyme fails to maintain normal ATP levels, producing severe hemolytic anemia. Here, we address the correction of PKD through precise gene editing at the PKLR endogenous locus. We combined CRISPR/Cas9 system and rAAVs to build an efficient and safe system to knock-in a therapeutic donor in the RPK isoform of human hematopoietic progenitors (HSPCs). Edited cells efficiently reconstituted human hematopoiesis in primary and secondary immunodeficient recipients. Moreover, erythroid cells derived from edited PKD-HSPCs restored normal levels of ATP, concluding that our gene editing strategy may represent a lifelong therapy to restore RPK functionality in RBCs of patients and correct PKD.

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